Cell
therapy — the infusion or grafting of cells in a patient's body to
replace those that have failed to function or to integrate those that
are missing — is neither a new clinical concept nor a
recently-introduced practice. Its archetype is the intravenous blood
transfusion carried out successfully after 1818, the year in which James
Blundel, the English gynecologist, introduced it as a treatment for
post-partum hemorrhage. The first treatment to use cells of a staminal
type (unspecialized pluripotent cells capable of self-maintenance in
culture and of differentiation into the cell lines that make up tissue
and organs), was a transplant of bone-marrow, which contains staminal
haematopoietic and mesenchymal elements.

Recent
remarkable developments in research on the properties, sources and
suitability for engineering of various types of stem cells, have led to
the prospect of an extension of cell therapy to the treatment of certain
metabolic, muscular, cardiovascular, neurological, neo-plastic and other
disorders. Although this goal has not yet been attained, its scientific
and clinical importance and the great human and Christian value of every
effort to alleviate the sufferings of the sick and offer a realistic
prospect of recovery to an increasing number of persons has attracted
more and more interest to this field of biomedical research; it has also
rapidly become the centre of a considerable investment of public and
private funds at both national and international levels.

At
the start of the new century that has not only seen the beginning of
systematic research laying the biological and clinical foundations for
therapy using stem cells or cells derived from them, but also the
intense confrontation that the moral implications of these
investigations have sparked among experts and in society, the Holy
Father recognizes this new frontier of transplant surgery as "a
great step forward in science's service to man" and "a valid
means of attaining the primary goal of all medicine — the service to
human life". However, the Pope also stresses that, "as with
all human advancement, this particular field of medical science, for all
the hope of health and life it offers to many, also presents certain
critical issues that need to be examined in the light of a discerning
anthropological and ethical reflection" (Address to the 18th
International Congress of the Transplantation Society, 29 August
2000; ORE, 30 August 2000,

pp.
1-2).

Among the critical
points that are currently the object of public debate as well as of
national laws and projects for international legislation, the matter of
the origin of the stem cells to be used for therapy arises. This issue
does not only provide for the biologically relevant and ethically
important distinction between human stem cells of the embryonic and
non-embryonic type (from an aborted fetus, perinatal and postnatal), but
must also deals with the possibility — contemplated by certain
research programmes — that the former type of cell may be taken from
embryos of gametic origin (in vitro fertilization), but removed
from embryos obtained for this purpose through cloning.

In
the address cited above, John Paul II also notes: "Science itself
points to other forms of therapeutic intervention which would not
involve cloning or the use of embryonic cells, but rather would make use
of stem cells taken from adults. This is the direction that research
must follow if it wishes to respect the dignity of each and every human
being, even at the embryonic stage" (ibid.). The Pope's
instruction, fully accessible to reason, is founded on two cornerstones;
the first, which is scientific, allows for the status quaestionis
of stem cell research, and recognizes the fundamental role that the
creativity of the researcher's investigative intelligence plays in
conceiving and closely examining various hypotheses for a solution to
the problem of cell therapy.

The
second, an ethical kind, admits that "once the moral species of an
action prohibited by a universal rule is concretely recognized, the only
morally good act is that of obeying the moral law and of refraining from
the action which it forbids" (Veritatis Splendor, n. 67).
The scientific and moral stature of biomedical researchers is built on
these two cornerstones: enthusiastic and tenacious openness to reality,
which can reveal unexpected and surprising therapeutic opportunities,
and an unfailing respect and love for the life and dignity of every
human being, which induces researchers firmly to reject every act that
intrinsically is contrary to them.

*****

Many factors interact at the genetic, biochemical,
cellular, hystological, physio-pathological and environmental levels in
the epigenetic and homeostatic processes that control the development
and health of an organism and permit the restitutio ad integrum
of its morphofunctional order. Consequently, scientific research and
clinical experimentation have a multitude of conceptual and operational
processes to choose from in order to achieve a specific objective, in
the case of cell therapy as in others.

Having
considered all the aspects of the illness and of the patient that are
ascertainable at a given historical moment, the researcher's ingenuity
and the clinician's fruitful intuition have always been able to discover
different or new possible solutions for previously unsolved or
under-treated problems. When faced with a wide range of possible paths
for investigation, all of which converge in the same end, the expert and
doctor — who are called to choose as the object of their clinical
activity and research what is "in conformity with the good of the
person with respect for the goods morally relevant for him" (Veritatis
Splendor, n. 78) — will have to exclude, in the first place, those
paths of investigation that demand morally illicit acts.

Such a decision takes the form of a rational
determination of morality in the conduct of researchers and clinicians.
"Without recognizing the legitimacy and need for such rational
determinations at a practical level, it would be impossible to agree on
any legislation for scientific research, worked out in view of its
content and binding without exception, and this would be to the
detriment of the common good and of respect for the fundamental
rights of every human being, starting with the right to life" (J.
Vial Correa and E. Sgreccia, Cellule Staminale Autologhe e
Trasferimento di Nucleo, in L'Osservatore Romano, 5 January
2001, p. 6).

Yet
some authors propose a revision of the ethics of biomedical research,
based on a different relationship between the researcher as a person and
his actions. They refer to the research scientist's "fundamental
freedom" that they believe is more radical than freedom of choice
with regard to specific acts; without considering this it would be
impossible to comprehend or evaluate the conduct of researchers.

This
"basic option" or "radical decision", which is
transcendental, would describe the commitment of both researcher and
doctor with regard to a good, recognized as "superior", that
deserves unconditional dedication and is often identified as a
"good of progress" (an increase in scientific knowledge and in
its diagnostic, therapeutic and preventative applications). It is also
identified as "a good of humanity" (the alleviation of
suffering by fighting disease, and the improvement of the expectations
and "quality of life"). The specific acts of researchers that
derive from this option would be merely temporary attempts to express
it. Their immediate object would be a "categorical good",
which — because of its partial nature — could not determine the
morality of the researcher as a person, even if it were only through the
realizing or rejecting of these endeavours or projects that every expert
could express his fundamental ethical choice.

Thus,
a separation is outlined in certain biomedical circles — and more
generally, in certain social sectors that promote and direct these
cultural trends — between the two levels of morality: the goodness or
malice of the researcher and doctor on the one hand, which would depend
on the intention motivating them and on their basic option with regard
to the engagement of "a service to science and humanity"; and
the rectitude or injustice of individual experimental acts, determined
by the calculation of proportionality between the good and evil,
"pre-moral" (or "physical"), inherent in or
consequent to the actions accomplished.

Given
the contingency of the goods connected with a research project or a
clinical protocol, it would be impossible to establish absolute moral
norms at the categorical level which forbid specific interventions
involving, for example, the production, manipulation and suppression of
an embryo in vitro.

Such
an ethic for research is based on an anthropology conditioned by a
spiritualist dualism that considers the person as primarily identified
with his

"absolute"
freedom which is self-determined or disconnected from any reference to
the corporal, historical or social dimension of his practice, whereas
human nature is seen as something sub- or pre-personal that does not
constitute a normative reference for the procedure. In fact, it is
impossible to separate the person from his acts (cf. K. Wojtyla, Persona
e Atto, Libreria Editrice Vaticana, 1980, pp. 131-174), nor can a
person's morality be disassociated from the quality of his actions:
"Idem sunt actus morales et actus humani?" (St Thomas
Aquinas, Summa Theologiae, I-II, q. 1, a. 3).

The
commitment of biomedical researchers to "the progress of
science" that fulfils their professional vocation in the service of
"the good of humanity" (or, more specifically, of humanity
suffering due to sickness), "to the extent that it is distinct from
a generic intention and hence one not yet determined in such a way that
freedom is obligated, is always brought into play through conscious and
free decisions", and "judgments about [their] morality cannot
be made without taking into consideration whether or not the deliberate
choice of a specific kind of behaviour is in conformity with the dignity
and integral vocation of the human person" (Veritatis Splendor,
n. 67).

The
negative moral precepts that prohibit semper et pro semper
"the direct and voluntary killing of an innocent human being",
based upon "that unwritten law which man, in the light of reason,
finds in his own heart (cf. Rom 2:14-15)" (John Paul II, Evangelium
Vitae, n. 57), do not leave room in any morally acceptable way for
the "creativity" of any contrary determination whatsoever (cf.
Veritatis Splendor, n. 67).

Instead,
they demand a "scientific creativity" that can identify new
sources of stem cells — equipped with sufficient potential for
reproduction and differentiation, and have the capacity to repair tissue
— that will pave the way to cell therapy without recourse to the
creation and destruction of human embryos.

Some people's argument, in the attempt to justify
the process of human cloning as a way of procuring embryonic stem cells
to be cultured, expanded and differentiated in vitro, appeals to three
biological applications: immunology, the potential for differentiation
and nuclear reprogramming. These fundamental applications are crucial to
the success of a therapeutic approach that uses stem cells; but, on
close examination, none of them is cogent. Indeed, for each application,
a reasonable and realistic alternative to cloning exists whose
scientific and clinical value is documented, also and increasingly, by
data published in the most recent top-level international literature in
this sector.

The
immunological application originated in the experience of transplant
clinics. Tissue or organ transplantation, when the donor and recipient
are not genetically compatible (as in the case of those who are not
close blood-relations) generally results in rejection of the graft;
immuno-suppressive treatment is required to prevent this. In the case of
cell therapy, the immunological barriers "are identical to those of
the allografts of tissue from conventional sources" (J.A. Bradley
et al., Nature Reviews Immunology 2002, 2: 859-871, p. 861).

The rejection is triggered by the allelomorphic
differences between the donor and the recipient in polymorphic loci that
give rise to histocompatible antigenes (groups ABO, HLA/MHC and mHC).
The hypothesis, prematurely proposed by some, that embryonic stem cells
possess an "immunological privilege" that allows them to be
tolerated by the recipient, was also doomed to failure because of the
discovery that they also express the protein MHC class I (M. Drukker et
al., Proceedings of the National Academy of Sciences USA 2002,
99: 9864-9869). The nuclear transfer of a somatic cell from a patient
who is a candidate for cell therapy to an oocite whose nucleus has
previously been removed (somatic cell nuclear transfer), and the
activation of the development process would make it possible to generate
a cloned human embryo with a nuclear genome identical to that of the
patient whose stem cells, removed at the stage of blastocyst, would be
compatible with those of the recipient, with the possible sole exception
of the mytochondrial genome.

However,
at least in laboratory animals, this heteroplasm does not seem to be an
obstacle to the compatibility required by a graft (R.P. Lanza et al., Nature
Biotechnology 2002, 20: 689696).

The
immunological problem that conditions the success of every possible cell
therapy can be addressed by other strategies appearing today on the
horizons of stem cell research.

The
first is the creation of stem cell "banks" that collect and
preserve the donations of a wide range of genetically different
subjects, from time to time seeking an immunological match between donor
and recipient, as the procedure for organ and tissue transplantation
currently requires. Immuno-suppressive interventions would make it
possible to overcome the immunological barrier that remains, in this
case too, because of an imperfect HLA identity between the graft and the
host. The number of immuno-suppressive agents is increasing, and in
recent years the survival rate of grafts has increased considerably,
although the risks connected with a non-specific depression of the
immune response (for example, the onset of opportunist infections)
remain.

The
genetic engineering of stem cells is a second possible way to get round
the immunological obstacle. One possibility is to obtain the cellular
phenotype of a "universal donor" by means of the deficiency of
expression of the MHC system (class I and class II) by the deletion or
modification of the corresponding genes or those that regulate the
transcription.

Another
approach should also be mentioned: this foresees the onset of tolerance
to the graft (the absence of a specific immunological reaction) in the
patient awaiting cell therapy, for example, by inducting a mixed
haematopoietic chimerism. As well as in rodent models, the latter
process has also found a clinical application in kidney transplants (M.T.
Millan et al., Transplantation 2002, 73: 1386-1391).

Lastly,
the most direct and reliable way to overcome the immunological obstacle
to cell therapy is the use of (autologous) stem cells from the same
patient, collected in the perinatal (from umbilical cord blood) or
postnatal (from somatic tissue) periods, and brought to differentiation
or transdifferentiation in vitro or in vivo in a cell line
required by the treatment of the pathology afflicting the patient.

One method, that of the autograft, has already
been successfully tested in the sectors of blood, bone marrow and skin,
but it is neither quick nor easy to achieve as all clinically
well-established cell therapy should be. In addition to perfect
tolerability, the process would also avoid the possible transmission of
infections. This prospect faces the second application proposed by those
who champion cloning for cell therapy: the potential for
differentiation.

Different
lines of stem cells, even if they have a common genetic heritage,
possess different potentials for replication (self-renewal and expansion
in vitro), epigenesis (differentiation into different cell lines)
and regeneration (functional reconstruction invivo of a
tissue) (I.L. Weisman, Science 2000, 287: 1442-1446; C.M.
Verfaille, Trends in Cell Biology 2002, 12: 502-508). In the
human scale of epigenetic potential, the zygote and blastomeres of the
embryo in its very earliest phases of segmentation occupy first place;
they are the only human cells that can independently lead to an organism
complete with all its tissues under specific conditions.

It
is possible to isolate from the internal cellular mass of the human
embryo at the blastocyst stage certain stem cells with less epigenetic
potential (pluripotent), but that can still differentiate to form a
mature lineage of cells that belongs to all three germ layers (ectoderm,
mesoderm, endoderm).

Embryonic
stem cells have also attracted attention because of their high
replicative potential (as many as 300-400 continuous cell divisions in
culture). Only very recently, however, has it been possible to
demonstrate that one type of differentiated cell (dopaminergic neuron)
that comes from the culture of rat stem cells has a regenerative
potential for Parkinson's Disease in the animal model (J.-H. Kim et al.,
Nature 2002, 418: 50-56), whereas it has not yet been proven that
other specialized cells derived from embryonic stem cells are
functionally able to reconstruct a tissue in vivo (N. Lumelsky et
al., Science 2001, 292: 1389-1394; M. Kyba et al., Cell
2002, 109: 29-37).

"It
is not surprising", observed Stuart H. Orkin and Sean J. Morrison,
"that cells generated in vitro are not equivalent to those
that are formed in vivo, considering the wide cellular
interactions and the 'education' [of cells] that takes place during an
organism's development" (Nature 2002, 418: 25-27, p. 25).

Moreover,
there is stronger evidence from experimentation on animals that
embryonic stem cells, precisely by virtue of their elevated replicative
and epigenetic potential, give way after the graft to an uncontrolled
neoplasmic proliferation, as has recently been soundly documented in the
case of teratomas (S. Wakitani et al., Rheumatology 2003, 42:
162-165). The rigorous exclusion of the presence of residues of
non-differentiated cells of an embryonic staminal type in cultures
destined for cell therapy, indispensable for the patient's safety, is a
matter that cannot be underestimated.

These
and other experimental considerations lead one to believe that the
choice of cloning as a biotechnological strategy for cell therapy is a
therapeutic approach containing serious difficulties and
contraindications, albeit, merely biological and clinical. The
insistence on this approach seems even more unjustifiable if one
considers that the alternative recourse to autologous stem cells of
perinatal and postnatal origin, dictated solely by the ethical
objections of a consistent number of citizens, is not a choice with any
less scientific value or fewer therapeutic prospects; its plausibility
and convenience can be found in the attentive and objective
consideration of the recent results of research in this sector.

Recently,
S. Pluchino and his associates (Nature 2003, 422: 688-694) have
elegantly demonstrated the therapeutic capacity of cultures of neural
stem cells taken from adult animals, by means of intrathecal or
intravenous injection, in a rat model chronically affected with multiple
sclerosis.

Lastly,
certain specialists, while rejecting the hypothesis of a cell therapy
based on the so-called "therapeutic" cloning, claim that a
temporary phase of experimentation with somatic cell nuclear transfer on
human beings is justified by the need to acquire information on
cytological factors that permit nuclear reprogramming, knowledge of
which, they say, is crucial for the effective differentiation,
dedifferentiation or transdifferentiation in vitro of stem cells
from adult tissue.

The
application of nuclear reprogramming is motivated by the attempt in
principle, biologically plausible and ethically acceptable, to obtain
multipotent or pluripotent non-embryonic stem cells, starting with stem
cells or pre-differentiated cells from adult tissue, through their
culture in cytoplasmatic conditions which have been made to resemble in
certain aspects the ooplasmic environment. This experimental project is
not the same as the reprogramming of the nucleus in an oocite (W. Shi et
al., Differentiation 2003, 71: 91-113), nor the fusion of a
somatic stem cell with an embryonic stem cell (M. Tada et al., Current
Biology 2001, 11: 1553-1558; Q. L. Ying et al., Nature 2002,
416: 545-548), both of which raise serious issues of grave moral
importance: the first, because of the development of a precocious
embryonic type (segmentation, compaction, cavitation), which the oocite
containing the nucleus would encounter; the second, in virtue of the use
of stem cells illegally obtained through the destruction of a human
embryo.

Nevertheless,
the identification of the ooplasmatic factors that facilitate nuclear
reprogramming can also occur experimentally in an animal model for
somatic cell nuclear transfer, and can be reapplied indirectly (through
the analysis of structural homology) to the human being.

Furthermore,
a certain initial success has been achieved in the attempt to induce
nuclear reprogramming that produces a cellular phenotype by fusion with
a differentiated cell (A. Medvinsky and A. Smith, Nature 2003,
422: 823-825) or with extracts from a cell also already differentiated
(A.M. Håkelien et al., Nature Biotechnology 2002, 20: 460-466).

It would therefore seem that recourse to human
cloning in order to learn how to reprogramme the nuclei of cells
destined for therapy is not indispensable.

In
the light of these considerations, the exclusion of human cloning from
research in cell therapy is a morally reasonable, scientifically
acceptable and socially responsible decision.

"In presenting the
moral orientations dictated by natural reason, the Church is convinced
that she offers a precious service to scientific research, doing her
utmost for the true good of the human person. In this perspective, she
recalls that, not only the aims, but also the methods and means of
research must always respect the dignity of every human being, at every
stage of his development and in every phase of experimentation"
(John Paul II, Address to Members of the Pontifical Academy for Life,
24 February 2003, n. 4; ORE, 5 March 2003, p. 4).

Taken from:
L'Osservatore Romano
Weekly Edition in English
24 September 2003, page 9

L'Osservatore Romano is the newspaper of the Holy See.
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